The field of the invention is methods of using cytokine antagonists to treat HIV infection and AIDS. In particular, the field of the invention is methods of treating HIV infection and AIDS using IL-4/IL-13 cytokine antagonists. The field of the invention also includes augmenting the efficacy of HIV vaccines by co-administration with IL-4/IL-13 cytokine antagonists.
AIDS (acquired immune deficiency syndrome) is caused by the human immunodeficiency virus (HIV). Most scientists think that HIV causes AIDS by directly killing CD4+T cells or interfering with their normal function, and by triggering other events that weaken a person""s immune function. It is widely thought that the HIV-specific cytotoxic T-lymphocytes (CTL) and T-helper cells play a central role in the control of viral replication (Reviewed by Ghandi and Walker 2002 Annu Rev Med 2002;53:149-72; Altfeld and Walker 2001 nature Medicine 8(7) 881-884). In addition, neutralizing antibodies play an apparently subordinate role in viral control (Poignard P et al. 1999 Immunity 10, 431-438). In fact, HIV elicits primarily a non-neutralizing antibody response in vivo that may provide a mechanism of immune escape (C. Grundner et al. 2002 9th Conference on Retroviruses and Opportunistic Infections, February 24-28, Abstract 105).
A number of drugs for the treatment of HIV infection have been approved over the past ten years. These drugs include nucleoside analog reverse transcriptase inhibitors (NRTIs), which interrupt an early stage of viral replication. Included in this class of drugs are zidovudine (AZT), didanosine (ddI), stavudine (D4T), lamivudine (3TC) and abacavir succinate. These drugs reduce the systemic viral load resulting from HIV infection and proliferation and thus reduce the frequency of opportunistic infections. Importantly, they do not prevent transmission of HIV to other individuals, though they do likely reduce the rate of transmission. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine and efavirenz are also available for use in combination with other antiretroviral drugs. Another class of drugs is called protease inhibitors, which interrupt viral replication at a later step in its life cycle. They include ritonavir, saquinivir, indinavir, amprenavir, lopinavir, and nelfinavir. Finally, a brand new class of drug called a fusion inhibitor has just been approved for use (T-20 or fuzeon). Because HIV can become resistant to each class of drugs, combination treatment is necessary to effectively suppress the virus. Currently available antiretroviral drugs do not cure HIV infection and they all have side effects that can be severe. A number of drugs are available to help treat the opportunistic infections people with HIV infection tend to develop. These drugs include foscarnet and gancyclovir, used to treat cytomegalovirus eye infections, fluconazole to treat yeast and other fungal infections, and TMP/SMX or pentamidine to treat Pneumocystis carinii pneumonia (PCP). HIV-infected individuals who develop Kaposi""s sarcoma or other cancers are treated with radiation, chemotherapy, or injections of alpha interferon, a genetically engineered naturally occurring protein.
Clearly, a need exists to develop additional therapies for HIV infection and AIDS treatment that are not subject to viral resistance and that have minimal side effects.
In one aspect, the invention features a method of treating HIV infection in a mammal comprising administering a cytokine antagonist to the mammal such that HIV infection is treated. In a preferred embodiment, the mammal is a human in need of treatment for HIV infection. In another aspect, the invention features treating a subject at risk of HIV infection comprising administering a cytokine antagonist to the subject.
In another embodiment, the cytokine antagonist is an IL-4/IL-13 trap. In still other embodiments, the cytokine antagonist is an IL-4 trap, an IL-13 trap, or anti-IL-4 antibodies or anti-IL-13 antibodies.
In one embodiment, the HIV infection is chronic infection. The chronic infection phase is characterized by multiple antibodies to HIV and a limited Th1/CTL response. In another embodiment, the HIV infection is acute infection. In the acute infection phase, antibodies have not yet developed and individuals, if treated appropriately, have a greater chance to become long-term non-progressors i.e. do not develop AIDS.
In another embodiment of the method of the invention, HIV infection is treated by blocking IL-4- and IL-13-mediated biological effects.
In a second aspect, the invention features a method of augmenting the efficacy of HIV vaccination in a human comprising administering an IL-4/IL-13 antagonist to the human such that the efficacy of HIV vaccination is augmented. In a specific embodiment, the IL-4/IL-13 antagonist is an IL-4/IL-13 trap. In still other specific embodiments, the cytokine antagonist is an IL-4 trap, an IL-13 trap, or anti-IL-4 antibodies or anti-IL-13 antibodies.
In a third aspect, the invention features a method of shifting the HIV vaccination-induced immune response in a human towards a Th1-type response, comprising co-administration of an IL-4/IL-13 antagonist and the vaccine to the human such that the HIV vaccination-induced immune response is shifted towards a Th1-type response. In a specific embodiment, the IL-4/IL-13 antagonist is an IL-4/IL-13 trap. In another specific embodiment, the cytokine antagonist is an IL-4 trap, an IL-13 trap, or anti-IL-4 antibodies or anti-IL-13 antibodies. Another embodiment is a method of treating HIV or AIDS comprising administering the cytokine antagonist, for example IL-4/IL-13 trap, in combination with anti-retroviral therapy, either by co-administraion or alternating administration.
In a fourth aspect, the invention features a method of shifting the Th2-type immune response to a Th1-type immune response in an HIV-infected human comprising administering an IL-4/IL-13 antagonist to the human such that the Th-2-type response is shifted to a Th1-type response in a specific embodiment, the IL-4/1L-13 antagonist is an IL-4/IL-13 trap. In other embodiments, the cytokine antagonist is an IL-4 trap, an IL-13 trap, or anti-IL-4 antibodies or anti-IL-13 antibodies.
In a related fifth aspect, the invention features a method of inhibiting the Th2-type immune response in an HIV-infected human comprising administering an IL-4/IL-13 antagonist to the human such that the Th-2-type response is inhibited. In a specific embodiment, the IL-4/IL-13 antagonist is an IL-4/IL-13 trap and n still other specific embodiments, the cytokine antagonist is an IL-4 trap, an IL-13 trap, or anti-IL-4 antibodies or anti-IL-13 antibodies.
Additional embodiments of the invention include methods wherein the administration is subcutaneous, intramuscular, intranasal, intrathecal, intraarterial, intravenous, topical, transvaginal, transdermal, or transanal administration.
In a sixth aspect, the invention features pharmaceutical compositions comprising an IL-4/IL-13 antagonist of the invention with a pharmaceutically acceptable carrier. Other objects and advantages will become apparent from a review of the ensuing detailed description.